METABOLIC PROBLEMS AND NEONATAL SEIZURES

DR. ELFADIL EISA IDRIS SULIMAN

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Introduction

• A neonatal seizure is a paroxysmal alteration in neurological functions (behavioral, motor, or autonomic) due to abnormal electrical activity in the immature brain.
• Occurs within the first 28 days of life (up to 44 weeks postconceptional age in preterm infants).
• Neonatal seizures are the most common neurological emergency in the newborn.
• They are a sign of underlying brain dysfunction, not a disease by themselves.
• Metabolic disturbances and Inborn Errors of Metabolism (IEM) are the most important causes.
• Although rare, early diagnosis is critical since some are treatable and recurrence can be prevented.

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Types of Neonatal Seizures

There are four main neonatal seizure types:

1. Subtle seizures
2. Clonic seizures
3. Tonic seizures
4. Myoclonic seizures

1. Subtle Seizures

• Most common type: Accounts for 50–70% of neonatal seizures.
• Population: Usually seen in preterm or asphyxiated infants.
• Recognition: Often difficult to recognize because movements are brief or minimal.
• EEG Correlation: Often not accompanied by EEG changes (brainstem release phenomena).
• Brainstem Release Phenomena:
  • Damage or dysfunction of higher brain centers (especially the cerebral cortex) removes their normal inhibitory control over the brainstem.
  • This allows primitive brainstem motor patterns to “break free” and become visible. The cortex normally suppresses brainstem reflex activity.
  • When the cortex is injured (e.g., hypoxia, ischemia, or metabolic injury), the brainstem becomes disinhibited and produces abnormal movements.
  • In neonates (especially preterm), cortical inhibitory pathways are immature while brainstem and subcortical structures are relatively well developed.
• Features of Subtle Seizures:
  • Ocular movements: Eye deviation, blinking, staring.
  • Oral movements: Sucking, chewing, lip-smacking.
  • Limb movements: Pedaling, rowing, swimming-like motions.
  • Autonomic signs: Apnea, changes in heart rate or blood pressure, flushing, pupillary dilatation.
• Mechanism:
  • Typical epileptic seizures due to cortical electrical discharges show EEG changes.
  • In subtle seizures, the origin is subcortical/brainstem, not generated by synchronized cortical neurons, thus often lacking a clear EEG correlate.
• Prognosis: Variable.

2. Clonic Seizures

• Second most common type.
• Features: Rhythmic jerking movements (1–3 per second).
  • Focal: Involving one limb, one side of the face, or one side of the body.
  • Multifocal: Jerks shift from one body part to another in a random fashion.
• EEG Correlation: Usually associated with EEG correlation, indicating a true cortical seizure.
• Common Causes: Focal brain injury (e.g., stroke, hemorrhage, hypoxia, infection).
• Prognosis: Fair to Good.

3. Tonic Seizures

• Features: Sustained muscle contraction lasting several seconds.
  • Focal tonic: Extension or flexion of one limb or eye deviation.
  • Generalized tonic: Extension of all limbs with opisthotonus.
• Population: Common in severely asphyxiated or preterm infants.
• EEG Correlation: Often may not have EEG correlation (brainstem origin).
• Prognosis: Often poor.

4. Myoclonic Seizures

• Features: Sudden, brief jerks of muscles or muscle groups (lightning-like).
• Types: May be focal, multifocal, or generalized.
• Associations: Usually associated with diffuse brain injury or severe metabolic disorders (e.g., Inborn Errors of Metabolism).
• EEG Correlation: Often EEG-positive.
• Prognosis: Carries a poor prognosis.

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Differential Diagnosis of Neonatal Seizures

1. Jitteriness (Tremors):
   • A benign, non-epileptic movement disorder.
   • Characterized by fine, rapid, tremulous movements of the limbs or jaw. It is not a seizure
   • Triggers: Crying, handling, and stimulation.
   • Key Difference: Stops when the limb is held or flexed.
   • Associations: Occurs in hypoglycemia, hypocalcemia, hypomagnesemia, and infants with narcotic withdrawal syndrome.
   • Absence of: No eye deviation or autonomic changes.
2. Benign Sleep Myoclonus:
   • Focal or generalized myoclonic limb jerks.
   • Key Feature: Does not involve the face; occurs only when the baby is falling asleep or waking up.
   • EEG: Normal.
   • Outcome: Resolves by age 4–6 months.
3. Apnea Spills:
   • Distinguished by the absence of tonic or clonic movements.

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EEG Classification of Neonatal Seizures

1. Clinical Seizures with Consistent EEG Events

• Clinical seizures occur in relationship to seizure activity recorded on EEG.
• Includes: Focal clonic, focal tonic, and some myoclonic seizures.
• Nature: These are clearly epileptic and likely to respond to anticonvulsant drugs.

2. Clinical Seizures with Inconsistent EEG Events

• Clinical seizures occur without corresponding seizure activity on EEG.
• Includes: All generalized tonic seizures, subtle seizures, and some myoclonic seizures.
• Context: These infants tend to be neurologically depressed or comatose due to HIE (Hypoxic-Ischemic Encephalopathy).
• Nature: Likely to be of non-epileptic origin; may not require or respond to anticonvulsant drugs.

3. Electric Seizures Without Clinical Seizures

• Characterized by marked abnormal EEG without clinical manifestations.
• Context: May develop in comatose infants not on anticonvulsants.
• Subclinical Seizures: Electric seizures may persist after the introduction of anticonvulsants even if focal tonic/clonic clinical signs disappear.

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Etiology of Neonatal Seizures

1. Hypoxic–Ischemic Encephalopathy (HIE)

• Also known as postasphyxial seizures.
• A common cause in full-term infants.
• Onset: Usually occurs 12–24 hours after birth asphyxia.
• Refractory: Often refractory to usual doses of anticonvulsant drugs.
• Associated Metabolic Issues: May also be due to hypoglycemia and hypocalcemia associated with neonatal asphyxia.

2. Intraventricular Hemorrhage (IVH)

• A common cause of seizures in premature infants.
• Onset: Often occurs between 1 and 3 days of age.
• Signs: Associated with bulging fontanel, hemorrhagic spinal fluid (CSF), anemia, lethargy, and coma.

3. Hypoglycemia

• Seizures occur when blood glucose levels decline to the lowest postnatal value.
• Timing: Usually 1–2 hours of age or 24–48 hours after poor nutritional intake.
• Response: Responds well to glucose administration.

Normal Glucose Homeostasis in the Neonate

• Brain Energy: Glucose is the main energy source for the brain; neonates utilize up to 90% of total glucose for the brain.
• Sources:
  • Maternal supply via placenta (until birth).
  • Post-birth: Cord clamping leads to sudden loss of maternal glucose.
  • Neonatal glucose drops to ~30 mg/dL (1.7 mmol/L) at 1–2 hours post-birth.
• Stabilization: Levels stabilize by 3–4 hours to >45 mg/dL (2.5 mmol/L) via:
  • Hepatic glycogenolysis: Breakdown of stored glycogen after birth.
  • Gluconeogenesis: Glucose production from amino acids, lactate, and glycerol.
  • Fat oxidation/Lipolysis: Ketone body production for energy during prolonged fasting.

Hormonal Regulation

• Decrease Glucose: Insulin (promotes storage).
• Increase Glucose: Glucagon, cortisol, growth hormone, and catecholamines (promote release/production).

Definition of Neonatal Hypoglycemia

• Term Infant:
  • Blood glucose < 40 mg/dL (2.2 mmol/L) in the first 24 hours.
  • < 45 mg/dL (2.5 mmol/L) after 24 hours of life.
• Preterm Infant:
  • < 40 mg/dL (2.2 mmol/L) at any time.
• Severe Hypoglycemia: Some guidelines use < 30 mg/dL (1.7 mmol/L) as a threshold for urgent intervention.

Causes of Neonatal Hypoglycemia

• A. Excess Insulin:
  • Infant of diabetic mother.
  • Islet cell hyperplasia.
  • Beckwith-Wiedemann syndrome.
• B. Decreased Glycogen Stores:
  • Preterm infant.
  • Small for Gestational Age (SGA).
  • Intrauterine Growth Restriction (IUGR).
• C. Defective Glucose Production:
  • Inborn Errors of Metabolism (IEM).
  • Adrenal or pituitary insufficiency.
• D. Increased Glucose Utilization:
  • Sepsis.
  • Hypothermia.

Clinical Features of Hypoglycemia

• Early onset (< 48h).
• Jitteriness, tremors, poor feeding, lethargy.
• Seizures, apnea, or cyanosis.

Diagnosis of Hypoglycemia

• Blood glucose, insulin, cortisol, and growth hormone levels.
• Ketones and lactate.
• Blood gas and ammonia.
• Urine for reducing substances (galactosemia).
• Plasma amino acids, endocrine profile, and organic acids (metabolic screen).
• Evaluation for infection.

Management

• Immediate glucose correction – give a 2.5 mL/kg bolus of 10 % dextrose IV, then start a continuous infusion at 6–8 mg/kg/min.
• Treat the underlying cause (e.g., infection, endocrine or metabolic disorder).
• Resume oral feeds once the patient is stable.
• Frequent glucose monitoring to ensure adequate control.

4. Hypocalcaemia and Hypomagnesemia

• Develops in high-risk infants and responds well to therapy.
• Hypocalcaemia: Reduces neuronal stability → Jitteriness, seizures, stridor.
• Hypomagnesemia: Interferes with PTH secretion and calcium regulation; often associated with hypocalcemia.

5. Infections

• Includes meningitis, encephalitis, or TORCH infections.

6. Sodium Imbalances

• Hyponatremia (Serum Sodium < 135 mEq/L): Cerebral edema from water retention → Lethargy, seizures.
• Hypernatremia (Serum Sodium > 150 mEq/L): Cellular dehydration → Irritability, seizures.

7. Potassium Imbalances

• Hypokalemia / Hyperkalemia: Leads to arrhythmias and muscle weakness.

8. Structural Brain Abnormalities

• Examples: Lissencephaly and Schizencephaly.

9. Inborn Errors of Metabolism (IEM)

• Examples: Urea cycle defects, Maple Syrup Urine Disease (MSUD), and Non-ketotic hyperglycinemia.
• Clinical Signs: Seizures associated with lethargy, acidosis, and a family history of infant death.

10. Mitochondrial Disorders / Energy Defects

11. Pyridoxine Dependency

• A rare autosomal recessive disorder.
• Features: Generalized clonic seizures shortly after birth with signs of fetal distress in utero.
• Resistance: Seizures are resistant to usual anticonvulsant drugs.
• Treatment: I.V. Pyridoxine 100–200 mg (bolus dose) abruptly stops seizures and normalizes EEG.
• Maintenance: Lifelong supplementation of oral pyridoxine (10 mg/day).
• Untreated: Persistent seizures and severe mental retardation.

12. Benign Familial Neonatal Seizures

• An autosomal dominant condition.
• Onset: Starts on the 2nd to 3rd day of life.
• Frequency: Seizure frequency of 10–20/day.
• Course: Patients are normal between seizures; seizures typically stop by 1–6 months of age.

13. Drug Withdrawal Seizures

• May occur in the delivery room or be delayed for several weeks due to prolonged drug excretion by neonates.
• Drugs: Barbiturates, benzodiazepines, heroin, and methadone (maternal intake).
• Features: Jitteriness, irritability, lethargy with clonic or myoclonic seizures.

14. Acid-Base Disturbances

• Metabolic Acidosis: Depressed CNS, hypotonia.
• Metabolic Alkalosis: Neuromuscular irritability.
• Respiratory Acidosis: CNS depression.
• Respiratory Alkalosis: Seizures, irritability.

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Investigations

1. First Line

• Metabolic: Blood glucose, serum electrolytes (calcium, magnesium, sodium, potassium).
• Systemic: FBC/culture, CRP, coagulation profile, and Liver Function Tests (LFT).
• Metabolic Screening:
  • Blood gases.
  • Serum ammonia and amino acids.
  • Urine toxicology, amino acids, and organic acids.
• Lumbar Puncture: CSF microscopy and culture (bacterial and viral PCR for Herpes Simplex and Enterovirus).
• Neurophysiology: EEG to identify electrographic seizures and monitor therapy response. Consider cerebral function monitor (aEEG/CFM).

2. Second Line

• Congenital infection screen (TORCH screen).
• Imaging: MRI scan, Computed Tomography (CT), or cerebral Ultrasonography (suspicion of ICH, structural abnormalities, or unexplained seizures).
• Trial of Pyridoxine: Preferably during EEG monitoring (diagnostic and therapeutic).
• Consultation: Contact the metabolic team for further advice.

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Management of Neonatal Seizures

Immediate Stabilization

• Ensure ABC (Airway, Breathing, Circulation).
• Immediate Glucose Correction: 2.5 mL/kg of 10% dextrose IV bolus, followed by continuous infusion (6–8 mg/kg/min).
• Treat Underlying Causes: Meningitis, hypoglycemia, hypocalcaemia, hypomagnesemia, hyponatremia, and Vitamin B6 (pyridoxine) deficiency/dependency.

Specific Therapies

• Pyridoxine (Vitamin B6): Trial in refractory neonatal seizures. (for b6 dependency)
• Biotin: For biotinidase deficiency.
• Carnitine: Supplementation in primary carnitine deficiency.

Anticonvulsant Therapy

• A. Phenobarbital (First Line):
  • Loading dose: 20–30 mg/kg I.V.
  • Maintenance dose: 5 mg/kg/24hr (divided into 2 doses).
• B. Phenytoin:
  • Alternative: Levetiracetam.
  • Loading dose: 10–20 mg/kg I.V.
  • Maintenance dose: 5 mg/kg/24hr (divided into 2 doses).
• C. Midazolam / Lorazepam:
  • 0.1–0.3 mg/kg followed by Phenobarbital or Phenytoin maintenance.
• D. Lidocaine

Long-Term Management

• Dietary modifications: Protein restriction in urea cycle defects or organic acidemias.
• Enzyme Replacement / Liver Transplant: In selected cases.
• Genetic Counseling: For families.

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Prognosis of Neonatal Seizures

• Determining Factors: Depends mainly on the primary cause and severity.
• Excellent Prognosis: Hypoglycemic infants of diabetic mothers or hypocalcaemia associated with excessive phosphate feeding.
• Poor Prognosis: Neonates with intractable seizures due to severe HIE or structural brain abnormalities; high risk of status epilepticus and early death.

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Clinical Suspicion for Metabolic Causes

Always suspect a metabolic cause if:

• Seizures are refractory to standard drugs.
• Associated with poor feeding, vomiting, or lethargy.
• Presence of metabolic acidosis or hyperammonemia.
• Positive family history of neonatal death.
• Note: Early metabolic screening saves lives.

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GOOD LUCK